title: BH3 profiling discriminates response to cytarabine-based treatment of acute myelogenous leukemia.
abstract: As acute myelogenous leukemia (AML) patient response to cytarabine-based standard-of-care treatment is variable, stratification into subgroups by biomarker-predicted response may lead to improved clinical outcomes. Here, we assess cell mitochondrial depolarization to proapoptotic signaling BH3-only peptides as a surrogate for the function of Bcl-2 family proteins to address clinical response to cytarabine-based therapy in patients with AML (N = 62). Peripheral blood mononuclear cell (PBMC) or bone marrow aspirate specimens were obtained from newly diagnosed patients with AML, viably preserved, and assayed by flow cytometry following BH3 profile assay with individual BH3 peptides. Mann-Whitney analysis indicates biomarker correlation with response to induction therapy: Notably, BIM priming was highly significant (P = 2 × 10(-6)) with a compelling sensitivity/specificity profile [area under curve (AUC) = 0.83; 95% confidence interval (CI), 0.73-0.94; P = 2 × 10(-10)]. Multivariate analysis indicates improved profiles for BIM readout + patient age (AUC = 0.89; 95% CI, 0.81-0.97) and BIM + patient age + cytogenetic status (AUC = 0.91; 95% CI, 0.83-0.98). When patients were stratified by cytogenetic status, BIM readout was significant for both intermediate (P = 0.0017; AUC = 0.88; 95% CI, 0.71-1.04) and unfavorable (P = 0.023; AUC = 0.79; 95% CI, 0.58-1.00) risk groups, demonstrating predictive power independent of cytogenetics. Additional analyses of secondary clinical endpoints displayed correlation between overall survival (P = 0.037) and event-free survival (P = 0.044) when patients were stratified into tertiles by BIM peptide response. Taken together, these results highlight the potential utility of BH3 profiling in personalized diagnostics of AML by offering actionable information for patient management decisions.
authors.affiliation: Corresponding Authors: Michael Andreeff, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 448, Houston, TX 77054. mandreef@mdanderson.org.
authors.forename: William E
authors.initials: WE
authors.lastname: Pierceall
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Carlson
authors.forename: Xuelin
authors.initials: X
authors.lastname: Huang
authors.forename: Noel
authors.initials: N
authors.lastname: Blake
authors.forename: Ryan
authors.initials: R
authors.lastname: Lena
authors.forename: Michael
authors.initials: M
authors.lastname: Elashoff
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cardone
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D015415:Biomarkers; D003561:Cytarabine / Q000008:administration & dosage; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012372:ROC Curve; D012074:Remission Induction; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; C474007:Bax protein (53-86); D000072224:Bcl-2-Like Protein 11; D015415:Biomarkers; D008565:Membrane Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D003561:Cytarabine